Mabuchi Tamaki, Shintani Norihito, Matsumura Shinji, Okuda-Ashitaka Emiko, Hashimoto Hitoshi, Muratani Tadatoshi, Minami Toshiaki, Baba Akemichi, Ito Seiji
Department of Medical Chemistry, Kansai Medical University, Moriguchi 570-8506, Japan.
J Neurosci. 2004 Aug 18;24(33):7283-91. doi: 10.1523/JNEUROSCI.0983-04.2004.
The prolonged sensitization of pain transmission after nerve injury by increasing excitability of spinal neurons and thereby promoting repair is an adaptive response of the body. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is widely distributed in the nervous system and implicated in neurotransmission, neural plasticity, and neurotrophic actions. Although PACAP is distributed in the spinal cord and dorsal root ganglia, a role of PACAP in pain responses remains essentially unknown. Here we show that mice lacking the PACAP gene (PACAP-/-) did not exhibit inflammatory pain induced by intraplantar injection of carrageenan or neuropathic pain induced by L5 spinal nerve transection, whereas they did retain normal nociceptive responses. Intrathecal administration of NMDA induced mechanical allodynia in wild-type mice, but not in PACAP-/- mice. The NMDA-induced allodynia in PACAP-/- mice was reproduced by simultaneous intrathecal injection of PACAP with NMDA. Concomitant with the increase in PACAP immunoreactivity after nerve injury, NADPH-dependent nitric oxide synthase (NOS) activity visualized by NADPH diaphorase histochemistry markedly increased in the superficial layer of the spinal cord of wild-type mice, which was not observed in PACAP-/- mice. Simultaneous addition of PACAP and NMDA caused translocation of neuronal NOS from the cytosol to the membrane and stimulated NO production in vitro. These results demonstrate that PACAP might promote the functional coupling of neuronal NOS to NMDA receptors for both inflammatory and neuropathic pain to occur.
通过增加脊髓神经元的兴奋性从而促进修复，来延长神经损伤后疼痛传递的致敏作用，是机体的一种适应性反应。神经肽垂体腺苷酸环化酶激活多肽（PACAP）广泛分布于神经系统，并参与神经传递、神经可塑性和神经营养作用。尽管PACAP分布于脊髓和背根神经节，但PACAP在疼痛反应中的作用仍基本未知。在此我们表明，缺乏PACAP基因的小鼠（PACAP-/-）不会表现出因足底注射角叉菜胶诱导的炎性疼痛或因L5脊髓神经横断诱导的神经性疼痛，而它们确实保留了正常的伤害性反应。鞘内注射NMDA在野生型小鼠中诱导出机械性异常性疼痛，但在PACAP-/-小鼠中则不会。在PACAP-/-小鼠中，通过鞘内同时注射PACAP和NMDA可重现NMDA诱导的异常性疼痛。与神经损伤后PACAP免疫反应性的增加相伴，通过NADPH黄递酶组织化学观察到的NADPH依赖性一氧化氮合酶（NOS）活性在野生型小鼠脊髓浅层显著增加，而在PACAP-/-小鼠中未观察到。同时添加PACAP和NMDA导致神经元型NOS从胞质溶胶转位到细胞膜，并在体外刺激NO的产生。这些结果表明，PACAP可能促进神经元型NOS与NMDA受体的功能偶联，从而引发炎性疼痛和神经性疼痛。
